Viscous Agent for Ophthalmic Use

ABSTRACT

An object of the present invention is to provide an eyedrop which has a relatively low viscosity before instillation but is thickened on the eyeball surface at instillation. The eyedrop containing a viscous agent for ophthalmic use, which comprises a combination of hydroxyethylcellulose and dextran, exhibits a specific and synergistic thickening effect in the coexistence of mucin. Therefore, the eyedrop of the present invention is thickened on the eyeball surface upon contact with mucin in the precorneal tear film at instillation, whereby a desired pharmacological efficacy or refreshing feel can be sustained.

TECHNICAL FIELD

The present invention relates to a viscous agent for ophthalmic usecomprising a combination of hydroxyethylcellulose and dextran. Further,the present invention relates to an eyedrop containing a viscous agentfor ophthalmic use comprising the combination of hydroxyethylcelluloseand dextran, characterized in that it is thickened upon contact withmucin in the precorneal tear film at instillation. Further, the presentinvention relates to a precorneal tear film stabilizer and an enhancerfor retention of eyedrop on the ocular surface, comprising thecombination of hydroxyethylcellulose and dextran.

BACKGROUND ART

It is known that an eyedrop is retained on the ocular surface for a longtime and a desired pharmacological efficacy, refreshing feel or the likeis sustained. When it has high viscosity, however, as the viscosity ofan eyedrop is higher, it is more difficult to instill the eyedrop andfeel in instillation is deteriorated.

The ocular surface is covered with the precorneal tear film composed ofthree layers, i.e., an oily layer, an aqueous layer and a mucin layer.The mucin layer located at the innermost layer of the precorneal tearfilm plays a role in allowing the precorneal tear film to adhere to theocular surface so as not to flow tears off. When the precorneal tearfilm becomes unstable due to disorder of the mucin layer, a dry areacalled “dry spot” appears within a short period of time just beforeblinking, therefore, dry eye symptoms accompanying dry feel oruncomfortable feel in the ocular area may be caused in some cases.

On the other hand, hydroxyethylcellulose is a cellulose derivativehaving a hydroxyethoxyl group, and is generally used as a viscous agentor a dispersant. Further, dextran is a polysaccharide obtained byfermentation of sucrose, and is generally used as a viscous agent or astabilizer for an eyedrop.

JP-A-2002-97129 discloses an invention which relates to an eyedropcomprising a refreshing component and a viscous agent, and examples ofthe viscous agent include ethylcellulose, hydroxyethylcellulose, dextranand the like. U.S. Pat. No. 6,572,849 discloses an invention whichrelates to a composition for ophthalmic use with a pH of 1.5 to 3.5having a self-preserving ability, and as additives thereof, polyethyleneglycol, hydroxypropylmethylcellulose, hydroxyethylcellulose, dextran andthe like are described therein.

However, neither one of the above-mentioned documents is directed to theone in which hydroxyethylcellulose and dextran are formulated incombination.

DISCLOSURE OF THE INVENTION Problems that the Invention is to Solve

With regard to the viscosity of an eyedrop, when an eyedrop with lowviscosity is instilled, it immediately flows out of the ocular surface,therefore, a desired pharmacological efficacy or refreshing feel cannotbe sustained. On the other hand, when the viscosity of an eyedrop ishigh, it is retained on the ocular surface for a long time. However,there is a tendency that the higher the viscosity of an eyedrop is, themore difficult the instillation is and feel in instillation isdeteriorated. Accordingly, there has been a demand for development of aneyedrop which has relatively low viscosity before instillation and isthickened on the ocular surface in instillation thereby to sustain adesired pharmacological efficacy or refreshing feel. There has also beena demand for development of an eyedrop which can stabilize theprecorneal tear film thereby to relieve dry feel and uncomfortable feelin the ocular area.

Means for Solving the Problems

The present inventors made intensive studies by focusing attention onthe fact that when an eyedrop is instilled, it comes into contact withthe precorneal tear film on the ocular surface, in particular mucin inthe precorneal tear film. As a result, it was found that an eyedropcontaining a viscous agent for ophthalmic use comprising a combinationof hydroxyethylcellulose and dextran exhibits a specific and synergisticthickening effect in the coexistence of mucin, and thus the presentinvention has been achieved. Further, the eyedrop containing a viscousagent for ophthalmic use of the present invention has an excellenteffect of stabilizing the precorneal tear film, which was found from theresults of a test on changes of corneal surface regularity index, whichwill be described later, therefore it is useful as a therapeutic agentfor dry eyes or artificial tears. Further, the viscous agent forophthalmic use of the present invention can also be used as a vehiclefor an eyedrop that provides comfortable feel in instillation or aneye-friendly eyewash.

The eyedrop containing a viscous agent for ophthalmic use of the presentinvention exhibits a specific and synergistic thickening effect in thecoexistence of mucin, which is presumed to be based on the event thatthe binding of the viscous agent for ophthalmic use comprising acombination of hydroxyethylcellulose and dextran to mucin on the ocularsurface is enhanced. When the viscous agent for ophthalmic use of thepresent invention is used as a vehicle for an eyedrop, the eyedrop hasan excellent action of enhancing retention of eyedrop on the ocularsurface, which was found from the results of a test for evaluation ofocular surface retention of eyedrop, which will be described later.Accordingly, it can be also applied to a drug delivery system whichenhances the retention of drugs in anterior segment of the eye andintraocular penetration of drugs.

The present invention relates to:

(1) a viscous agent for ophthalmic use comprising a combination ofhydroxyethylcellulose and dextran;

(2) an eyedrop containing a viscous agent for ophthalmic use comprisinga combination of hydroxyethylcellulose and dextran;

(3) the eyedrop according to the above (2), wherein the pH thereof is inthe range of 4 to 8;

(4) the eyedrop according to the above (2), wherein the concentration ofhydroxyethylcellulose is in the range of 0.001 to 10% (w/v) and theconcentration of dextran is in the range of 0.001 to 10% (w/v);

(5) the eyedrop according to the above (2), wherein the pH thereof is inthe range of 4 to 8, the concentration of hydroxyethylcellulose is inthe range of 0.001 to 10% (w/v), and the concentration of dextran is inthe range of 0.001 to 10% (w/v);

(6) a viscous agent comprising a combination of hydroxyethylcelluloseand dextran, characterized in that it is thickened in the presence ofmucin;

(7) an eyedrop containing a viscous agent for ophthalmic use comprisinga combination of hydroxyethylcellulose and dextran, characterized inthat the eyedrop is thickened upon contact with mucin in a precornealtear film at instillation;

(8) a precorneal tear film stabilizer comprising a combination ofhydroxyethylcellulose and dextran;

(9) a system for stabilizing a precorneal tear film on an ocular surfaceby instilling an eyedrop containing a precorneal tear film stabilizercomprising a combination of hydroxyethylcellulose and dextran;

(10) an enhancer for retention of eyedrop on an ocular surface,comprising a combination of hydroxyethylcellulose and dextran;

(11) a system for enhancing the retention of drugs in anterior segmentof the eye by instilling an eyedrop containing an enhancer for retentionof eyedrop on an ocular surface comprising a combination ofhydroxyethylcellulose and dextran;

(12) a method of treating an eye disease comprising administering aneyedrop containing hydroxyethylcellulose and dextran to a patient in aneffective amount thereof for the treatment;

(13) a method of stabilizing a precorneal tear film on an ocular surfacecomprising instilling an eyedrop containing hydroxyethylcellulose anddextran to a patient; and

(14) a method of enhancing the retention of drugs in anterior segment ofthe eye comprising instilling an eyedrop containinghydroxyethylcellulose and dextran to a patient.

The eyedrop containing a viscous agent for ophthalmic use comprising acombination of hydroxyethylcellulose and dextran of the presentinvention exhibits a specific and synergistic thickening effect in thepresence of mucin, therefore, the eyedrop is thickened on the ocularsurface upon contact with mucin in the precorneal tear film atinstillation, whereby a desired pharmacological efficacy or refreshingfeel can be sustained. Further, since the eyedrop of the presentinvention stabilizes the precorneal tear film, it is useful forrelieving dry feel or uncomfortable feel in the ocular area, which leadsto improvement of dry eye symptoms. As will be described in detail laterin the section of “test for measurement of viscosity in the coexistenceof mucin” while a viscous agent comprising a combination ofhydroxyethylcellulose and dextran exhibits a specific and synergisticthickening action in the presence of mucin, a viscous agent comprising acombination of hydroxypropylmethylcellulose with dextran, which isanother cellulosic viscous agent, does not exhibit a synergisticthickening action. Accordingly, it is found that the synergisticthickening action is based on a specific property ofhydroxyethylcellulose.

In the viscous agent, the precorneal tear film stabilizer and theenhancer for retention of eyedrop on the ocular surface comprising acombination of hydroxyethylcellulose and dextran according to thepresent invention, the weight ratio of hydroxyethylcellulose to dextranis preferably 0.001 to 10 of hydroxyethylcellulose to 0.001 to 10 ofdextran, more preferably 0.01 to 5 of hydroxyethylcellulose to 0.005 to3 of dextran.

The hydroxyethylcellulose to be used in the present invention is acellulosic polymer and is available in various viscosities, and any ofthem can be used. The concentration of hydroxyethylcellulose in theeyedrop is not particularly limited. However, from the viewpoint of theproperties or effects of the eyedrop, it is in the range of 0.001 to 10%(w/v), more preferably in the range of 0.01 to 5% (w/v).

The dextran to be used in the present invention is a polysaccharideobtained by fermentation of sucrose and is available in various averagemolecular weights, and any of them can be used. Preferred examplesinclude dextran 40 (average molecular weight of about 40,000) anddextran 70 (average molecular weight of about 70,000). The concentrationof dextran in the eyedrop is not particularly limited. However, from theviewpoint of the properties or effects of the eyedrop, it is in therange of 0.001 to 10% (w/v), more preferably in the range of 0.005 to 3%(w/v).

The eyedrop containing the viscous agent for ophthalmic use, theprecorneal tear film stabilizer or the enhancer for retention of eyedropon the ocular surface comprising a combination of hydroxyethylcelluloseand dextran according to the present invention can be prepared using awidely used technique. Preferred preparations are eyedrops.

In the eyedrop of the present invention, a drug can be formulated.Examples of the drug include an antibacterial agent, anantiinflammatory, an antihistamine, an antiglaucoma agent, anantiallergic agent, an immunosuppressive agent, an antimetabolite andthe like.

In the eyedrop of the present invention, a tonicity agent, a buffer, apH adjustor, a solubilizer, a stabilizer, a preservative or the like canbe added as needed.

Examples of the tonicity agent include glycerol, propylene glycol,sodium chloride, potassium chloride, sorbitol, mannitol and the like.

Examples of the buffer include phosphoric acid, citric acid, aceticacid, e-aminocaproic acid, boric acid, borax, trometamol and the like.

Examples of the pH adjustor include hydrochloric acid, citric acid,phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide,boric acid, borax, sodium carbonate, sodium hydrogencarbonate and thelike.

Examples of the solubilizer to be added in the case, for example, wherea drug or another additive is hardly soluble in water includepolysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol4000 and the like.

Examples of the stabilizer include edetic acid, sodium edetate and thelike.

Examples of the preservative include sorbic acid, potassium sorbate,benzalkonium chloride, benzethonium chloride, methyl p-oxybenzoate,propyl p-oxybenzoate, chlorobutanol and the like. These preservativescan also be used in combination.

The pH of the eyedrop of the present invention is preferably set withinthe range of 4.0 to 8.0. In addition, the osmotic pressure rate ispreferably set at around 1.0.

The instillation frequency of the eyedrop of the present invention canproperly be selected depending on the symptoms, age, dosage form or thelike, however, it may be instilled once to about six times daily.

ADVANTAGEOUS EFFECTS OF THE INVENTION

As will be described in detail later in the section of “test formeasurement of viscosity in the coexistence of mucin”, the eyedropcontaining the viscous agent for ophthalmic use comprising a combinationof hydroxyethylcellulose and dextran of the present invention exhibits aspecific and synergistic thickening action in the coexistence of mucin.Therefore, the eyedrop of the present invention is thickened on theocular surface upon contact with mucin in the precorneal tear film atinstillation, whereby a desired pharmacological efficacy, refreshingfeel or the like can be sustained. Further, as is apparent from theresults of a test for evaluation of ocular surface retention of eyedropand a test on changes of corneal surface regularity index, the eyedropcontaining the viscous agent for ophthalmic use of the present inventionis excellent in the retention of drugs in anterior segment of the eyeand has an effect of stabilizing the precorneal tear film thereby torelieve dry feel in the ocular area. Therefore, it is useful forrelieving dry feel or uncomfortable feel in the ocular area as anenhancer for retention of eyedrop on the ocular surface, a precornealtear film stabilizer, a therapeutic agent for dry eyes or artificialtears. Further, it is also useful as a vehicle for an eyedrop thatprovides comfortable feel in instillation or an eye-friendly eyewash.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail byreferring to Examples, however, these examples are for understanding theinvention well, and are not meant to limit the scope of the invention.

[1] Test for Measurement of Viscosity in the Coexistence of Mucin

This test is to evaluate a synergistic thickening action in the casewhere test solutions are brought into contact with a mucin solutionrespectively by measuring the viscosity in the coexistence of each testsolution and mucin in accordance with the test method described inPharmaceutical Research, 491-495, Vol. 7, No. 5, 1990.

(Experimental Method)

As shown in Table 1, physiological saline was prepared and testsolutions 1 to 6 were prepared by dissolving each viscous agent inphysiological saline. Further, mucin (manufactured by SIGMA) wasdissolved in 0.1 M phosphate buffer to give a pH equal to that of tears(neutral pH), whereby 4% mucin solution (pH 7.0) was prepared. TABLE 1Viscous agent (%) Test solution 1 physiological saline (control) Testsolution 2 hydroxyethylcellulose (0.2) Test solution 3hydroxypropylmethylcellulose (0.25) Test solution 4 dextran (0.1) Testsolution 5 hydroxypropylmethylcellulose (0.25) + dextran (0.1) Testsolution 6 hydroxyethylcellulose (0.2) + dextran (0.1)

Then, using a rotary viscometer (Rheostress RS100, manufactured byHAAKE), the viscosities (π1, π2 and π3) at a shear rate of 100 S⁻¹ whenthe shear rate was increased from 0.1 to 150 S⁻¹ in 2.5 minutes weremeasured for respective solutions of a mixed solution of each testsolution (2 mL) and 4% mucin solution (6 mL), amixed solution of eachtest solution (2 mL) and 0.1 M phosphate buffer (6 mL) and a mixedsolution of water (2 mL) and 4% mucin solution (6 mL).

π1: viscosity of a mixed solution of each test solution (2 mL) and 4%mucin solution (6 mL)

n2; viscosity of a mixed solution of each test solution (2 mL) and 0.1 Mphosphate buffer (6 mL)

π3! viscosity of a mixed solution of water (2 mL) and 4% mucin solution(6 mL)

(Results)

In accordance with the following equation, the viscosity increase rateof each mixed solution was calculated. These results are shown in Table2.Viscosity increase rate=(π1−π2−π3)/π2×100

Incidentally, in the case where π1 is substantially the same π2 and π3,that is, there is almost no change in viscosity, the viscosity increaserate calculated from the above equation is around −100%. Further, in thecase where π1 obviously increases compared with π2 and π3, that is, π1is synergistically thickened, the viscosity increase rate calculatedfrom the above equation becomes a positive value. TABLE 2 Test solutionViscosity increase rate (%) Test solution 1 −105 Test solution 2 −31Test solution 3 −21 Test solution 4 −93 Test solution 5 −47 Testsolution 6 +22

(Discussion)

In the case where a viscous agent comprising a combination ofhydroxyethylcellulose and dextran was allowed to coexist with mucin, aspecific and synergistic thickening action was exhibited (test solution6). However, when physiological saline, hydroxyethylcellulose,hydroxypropylmethylcellulose or dextran was allowed to coexist withmucin respectively, a synergistic thickening action was not exhibited(test solutions 1 to 4). Further, when a mixture ofhydroxypropylmethylcellulose and dextran was allowed to coexist withmucin, a synergistic thickening action was not exhibited (test solution5).

[2] Test on Changes of Corneal Surface Regularity Index

In this test, corneal surface irregularities (irregularities of theprecorneal tear film) after instilling each test solution were measuredwith a corneal shape measurement device for the purpose of evaluating aprecorneal tear film stabilizing effect of each test solution.

(Experimental Method)

A 20 μL portion of the test solution 1 or the test solution 6 wasinstilled to male Japanese white rabbits under systemic anesthesia,followed by measuring of the corneal surface shapes at 0 (immediatelyafter instillation) and 10 minutes after instillation with the eyelidsforcibly retracted, with a corneal shape measurement device (TMS-2N,manufactured by Tomey Corporation).

(Results)

Based on the measured surface regularity index (surface regularity indexis increased with an increase in irregularity of the shape of theprecorneal tear film on the corneal surface), surface regularity indexchanges (a surface regularity index change means a value obtained bysubtracting the surface regularity index immediately after instillationfrom the surface regularity index 10 minutes after instillation) werecalculated. The results are shown in Table 3. Note that the surfaceregularity index change of each of the test solutions is an averagevalue of the three or five values. TABLE 3 Change of surface regularityTest solution index after 10 minutes Test solution 1 0.81 Test solution6 0.37

(Discussion)

As is apparent from Table 3, the test solution 6 containing a viscousagent comprising a combination of hydroxyethylcellulose and dextranexhibited a significant effect of stabilizing the precorneal tear filmcompared with physiological saline.(test solution 1).

[3] Test for Evaluation of Retention of Eyedrop on Ocular Surface

This test is to evaluate an action of ocular surface retention of eachtest eyedrop by measuring the fluorescence intensity in the precornealtear film with a fluorophotometer for the anterior segment of the eyeafter the test eyedrop was instilled.

(Experimental Method)

A 20 μL portion of the test solution 1 or the test solution 6 containing0.002% sodium fluorescein respectively was instilled to male Japanesewhite rabbits under systemic anesthesia, followed by measuring of thefluorescence intensity in the precorneal tear film at every 30 secondsfrom 0 minute (immediately after instillation) to 5 minutes afterinstillation, at every 1 minute from 5 minutes to 10 minutes afterinstillation and at every 5 minutes from 10 minutes to 30 minutes afterinstillation with the eyelids forcibly retracted, with afluorophotometer for the anterior segment of the eye (FL-500, Kowa).

(Results)

Based on the measured fluorescence intensity in the precorneal tearfilm, the average value of residual ratio of fluorescence intensity(which is a ratio of fluorescence intensity in each measurement time,when the fluorescence intensity immediately after instillation isassumed 100%) was calculated (an average of four cases each). Further, anoncompartmental analysis was carried out using the calculated averagevalue, and λz (which indicates an elimination rate, wherein the smallerthe value is, the longer the retention is) in the period fromimmediately after instillation to 2 minutes after instillation and AUC(which indicates an area under the fluorescence intensity vs. timecurve, wherein the larger the value is, the longer the retention is) inthe period from immediately after instillation to 30 minutes afterinstillation were calculated. The results of the measurement offluorescence intensity and the results of the analysis are shown in FIG.1 and Table 4, respectively. TABLE 4 Eyedrop λz₀₋₂ AUC₀₋₃₀ Test solution1 0.6194 431.3 Test solution 6 0.4639 611.7

(Discussion)

As is apparent from FIG. 1 and Table 4, the test solution 6 containing aviscous agent comprising a combination of hydroxyethylcellulose anddextran exhibited high ocular surface retention compared withphysiological saline (test solution 1).

FORMULATION EXAMPLES

Representative formulation examples obtained by formulating a viscousagent for ophthalmic use comprising a combination ofhydroxyethylcellulose and dextran are shown below.

Formulation Example 1 Eyedrop

In 100 ml, hydroxyethylcellulose 500 mg dextran 300 mg sodiumdihydrogenphosphate dihydrate q.s. 1 N sodium hydroxide q.s.hydrochloric acid q.s. sterile purified water q.s.

An eyedrop containing 100 mg, 1 g, 3 g or 5 g of hydroxyethylcellulosein 100 ml can be prepared in the same manner as the above formulationexample.

Formulation Example 2 Eyedrop

In 100 ml, hydroxyethylcellulose 300 mg dextran 300 mg sodiumdihydrogenphosphate dihydrate q.s. 1 N sodium hydroxide q.s.hydrochloric acid q.s. sterile purified water q.S.

An eyedrop containing 50 mg, 100 mg, 500 mg or 1 g of dextran in 100 mlcan be prepared in the same manner as the above formulation example.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing a relationship between residual ratio offluorescence intensity on the ocular surface (precorneal tear film) andtime in the case of using the test solution 1 and the test solution 6.

1. A viscous agent for ophthalmic use comprising a combination ofhydroxyethylcellulose and dextran.
 2. An eyedrop containing a viscousagent for ophthalmic use comprising a combination ofhydroxyethylcellulose and dextran.
 3. The eyedrop according to claim 2,wherein the pH thereof is in the range of 4 to
 8. 4. The eyedropaccording to claim 2, wherein the concentration of hydroxyethylcelluloseis in the range of 0.001 to 10% (w/v) and the concentration of dextranis in the range of 0:001 to 10% (w/v).
 5. The eyedrop according to claim2, wherein the pH thereof is in the range of 4 to 8, the concentrationof hydroxyethylcellulose is in the range of 0.001 to 10% (w/v), and theconcentration of dextran is in the range of 0.001 to 10% (w/v).
 6. Aviscous agent comprising a combination of hydroxyethylcellulose anddextran, characterized in that it is thickened in the presence of mucin.7. An eyedrop containing a viscous agent for ophthalmic use comprising acombination of hydroxyethylcellulose and dextran, characterized in thatthe eyedrop is thickened upon contact with mucin in a precorneal tearfilm at instillation.
 8. A precorneal tear film stabilizer comprising acombination of hydroxyethylcellulose and dextran.
 9. A system forstabilizing a precorneal tear film on an ocular surface by instilling aneyedrop containing a precorneal tear film stabilizer comprising acombination of hydroxyethylcellulose and dextran.
 10. An enhancer forretention of eyedrop on an ocular surface, comprising a combination ofhydroxyethylcellulose and dextran.
 11. A system for enhancing theretention of drugs in anterior segment of the eye by instilling aneyedrop containing an enhancer for retention of eyedrop on an ocularsurface comprising a combination of hydroxyethylcellulose and dextran.12. A method of treating an eye disease comprising administering aneyedrop containing hydroxyethylcellulose and dextran to a patient in aneffective amount thereof for the treatment.
 13. A method of stabilizinga precorneal tear film on an ocular surface comprising instilling aneyedrop containing hydroxyethylcellulose and dextran to a patient.
 14. Amethod of enhancing the retention of drugs in anterior segment of theeye comprising instilling an eyedrop containing hydroxyethylcelluloseand dextran to a patient.